Alcohol dependence is one of the most common addictive diseases and known to be in part genetically transmitted, based on an oligogenic background in which each gene involved contributes only little to the resulting phenotype. Besides influencing other signal transduction mechanisms, alcohol specifically inhibits the NMDA signaling cascade, which mediates the excitatory effects of glutamate in the brain. Target molecules, sensitive to ethanol, include the NMDA receptors as well as downstream molecules of the glutamatergic system, glutamate transporters, and associated regulatory proteins. Adaptive processes of the glutamatergic system during chronic alcohol consumption may play a major role for later development of reward symptoms. Candidate gene studies, including association studies and animal models, are powerful and sensitive for detecting oligogenic effects and thus important to alcoholism research.